Deepu Madduri, MD – Assistant Professor, Hematology and Medical Oncology of the Mount Sinai Hospital, Mount Sinai Beth Israel discusses ASH 2020 abstract – New data for CAR-T therapy cilta-cel include longer-term data from the Ph1b portion of the CARTITUDE-1 study and the first presentation of results from the Ph2 portion (Abstract #177) "“ these are the registrational data being submitted to regulatory authorities "“ plus detailed analyses of CRS and health-related QoL outcomes.
Context:
Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells) is a 2 B-cell maturation antigen chimeric antigen receptor T (CAR-T) cell therapy targeting single-domain antibodies intended to confer avidity. LCAR-B38M yielded deep, durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) in phase 1 LEGEND-2 study in China. The Step 1b/2 CARTITUDE-1 research (NCT03548207) in this pt population in the US is further evaluating cilta-cel. Along with the initial phase 2 data, we present updated data from the phase 1b section.
Methodology:
Qualified pts (aged ⇠18 y) were diagnosed with MM according to the requirements of the International Myeloma Working Group (IMWG) and had the detectable disease, success status of the Eastern Cooperative Oncology Group ⇠1, received ⇠3 previous regimens or double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. Bridging therapy was allowed after apheresis. For lymphodepletion, cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 were used daily for a duration of 3 d. A single infusion of cilta-cel was administered at a target dose of 0.75-106 (range 0.5-1.0-106) CAR+ viable T cells/kg 5-7 d after the onset of lymphodepletion. The primary objective of phase 1b was to define the protection of cilta-cel and to determine the prescribed phase 2 dose; the primary objective of phase 2 was to assess the efficacy of cilta-cel. The answer was assessed by next-generation sequencing according to IMWG criteria and minimal residual disease (MRD). The grading of adverse events (AEs) was performed using CTCAE v5.0.0. Cytokine release syndrome (CRS) was classified by Lee et al (Blood 2014) in the phase 1b portion and neurotoxicity by CTCAE v5.0; CRS and neurotoxicity were graded by the American Society for Transplantation and Cellular Therapy (ASTCT) criteria in the phase 2 portion. Lee et al and CTCAE v5.0 were mapped to ASTCT parameters for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively, in this combined study.
Outcomes:
As of the 20 May 2020 clinical cutoff, cilta-celta-celta MM earned 97 pts (58.8 percent male; median age 61.0 y [range 43-78]) with R/R MM (29 in phase 1b; 68 in phase 2). 8.8 mo (range 1.5-20.4) was the median follow-up length. A median of 6 prior therapy lines (range 3-18) was obtained by Pts; 83.5 percent were penta-exposed, 87.6 percent were triple-refractory, 41.2 percent were penta-refractory, and 97.9 percent were refractory to the last therapy line. The total response rate per independent review committee (primary endpoint) was 94.8 percent (95 percent CI 88.4-98.3), with a strict 55.7 percent complete response rate (95 percent CI 45.2-65.8), a very strong 32.0 percent partial response rate (95 percent CI 22.9-42.2), and a 7.2 percent partial response rate (95 percent CI 3.0-14.3). A decrease in M-protein was reached by all pts. The median time to first answer was 1.0 mo (range 0.9-5.8; 80.4% ⇠1.0 mo) and the median time to complete or better response was 1.8 mo (range 0.9-12.5; 74.1% ⇠3.0 mo); responses deepened over time (Figure). The median response period was not reached (NR). 94.2 percent were MRD-negative at 10-5 out of 52 MRD-evaluable pts. The rates of 6-mo progression-free survival (PFS) and overall survival (OS) (95% CI) were 87.4% (78.9-92.7) and 93.8% (86.7-97.2), respectively; NR was the median PFS and OS. During the study 10 deaths occurred; 8 were due to AEs (both linked and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, pulmonary abscess, and acute myelogenous leukemia [n=1 each and 2 were due to progressive illness. CRS (94.8 percent; grade [gr] 3/4 4.1 percent), neutropenia (90.7 percent; gr 3/4 90.7 percent), anemia (81.4 percent; gr 3/4 68.0 percent), and thrombocytopenia (79.4 percent; gr 3/4 59.8 percent) were AEs reported in >70% of pts. The median time to the onset of CRS was 7.0 d (range 1-12) and 4.0 d (range 1-27, except n=1 with 97 d) median period. In 20.6 percent of pts (gr 3/4 10.3 percent), CAR-T cell-related neurotoxicity was recorded. At 14 d (range 9"“43), Cilta-cel CAR+ T cells showed maximum peripheral expansion. Among pts with 6 mo’ individual follow-up, in peripheral blood, 67 percent had cilta-cel CAR+ T cells below the quantification stage 2 cells/μL).
Findings:
Preliminary phase 1b/2 CARTITUDE-1 results indicate that a single low-dose infusion of cilta-cel leads to early, deep, and long-lasting responses with a safety profile consistent with LEGEND-2 in heavily pretreated MM pts. Further investigation of cilta-cel is ongoing in other MM populations.