Ciltacabtagene autoleucel demonstrated a significant response rate and showed a manageable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma.
Deepu Madduri, MD
Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) demonstrated a significant response rate and showed a manageable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma, according to combined results from the CARTITUDE-1 trial (NCT03548207).1
The objective response rate (ORR) was 96.9%, consisting of stringent complete responses (sCRs) in 67.0% of patients, very good partial responses in 25.8%, and partial responses in 4.1%.
“We saw how heavily pretreated these patients were, and to see a one-time treatment give these kinds of response rates is quite exceptional,” said Deepu Madduri, MD, in a presentation during the 2020 American Society of Hematology (ASH) Annual Meeting. “What’s even more impressive is that 72% of these patients are still maintaining their response at the time of data cut off.”
Cilta-cel is a second-generation chimeric antigen receptor (CAR) T-cell therapy consisting of a CD3ζ signaling domain, a 4-1BB costimulatory domain, and 2 B-cell maturation antigen (BCMA) binding domains.
CARTITUDE-1 is a phase 1b/2 study exploring the safety and efficacy of cilta-cel in patients with progressive multiple myeloma per IMWG criteria who have received at least 3 prior therapies—including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy—or who are double refractory, and have an ECOG performance status of 0 or 1.
Once patients were screened and enrolled in the study, they underwent apheresis and bridging therapy, if necessary, followed by lymphodepleting chemotherapy of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 on days –5 to –3 prior to CAR T-cell infusion. The target dose was 0.75 x 106 viable CAR-positive T cells/kg, but the median dose administered was 0.71 x 106 (range, 0.51-0.95 x 106).
Primary objectives for the phase 1b portion of the study were to characterize the safety of the agent and set the recommended phase 2 dose; and in phase 2, the primary end point was to evaluate efficacy by ORR.
Previously, results of the phase 1b portion of the study were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showing responses in all 29 patients, including a very good partial response or higher rate of 97%.2
The presentation at ASH covered findings for all patients treated with cilta-cel in the phase 1b and 2 portions of the study (N = 97). Of these patients, 86% are still on the trial.
Median turnaround time for cilta-cel manufacturing was 29 days, and no patients discontinued from the study due to manufacturing failure.
At baseline, the median age of all patients was 61 (range, 43-78), 58.8% were male, and 13.4% had extramedullary disease. Almost one-fourth of patients (23.7%) had a high-risk cytogenetic profile, most often including del(17p), and 91.9% had tumor BCMA expression of at least 50%. The median number of prior therapies was 6 (range, 3-18), indicating a heavily pretreated population, with 87.6% being triple-class refractory and 42.3% being penta-refractory. Ninety-nine percent of patients were refractory to their last line of therapy, which was not required for inclusion in this study, noted Madduri. Additionally, 89.7% previously underwent autologous stem cell transplant and 8.2% received allogenic transplant.
Responses were ongoing at cutoff in 72.2% of patients and the median time to first response was 1 month (range, 0.9-8.5). Of 57 patients evaluable for minimal residual disease (MRD), the negativity rate at 10-5 was 93.0%, accounting for 54.6% of the overall population. A total of 33 patients (34.0%) achieved both sCR and MRD negativity. The median time to MRD negativity was also 1 month (range, 0.8-7.7).
“Early, deep, and durable responses are observed in this heavily pretreated population,” said Madduri, who is an assistant professor of medicine, hematology, and medical oncology at Mount Sinai Medical Center in New York.
The median progression-free survival (PFS) was not reached in responders but at 12 months, the PFS rate was 76.6% (95% CI, 66.0%-84.3%). In those who achieved an sCR, the 12-month PFS rate was 84.5% (95% CI, 72.0%-91.8%) and was 68.0% (95% CI, 46.1%-82.5%) in patients who had a very good partial response.
“Patients with relapsed/refractory myeloma have a median overall survival of only 9.2 months in triple-refractory [disease] and only 5.6 months in penta-refractory. In this study, we know that the median PFS is at least a full year and we still haven't even reached a median PFS after a median duration of follow-up of 12.4 months,” Madduri commented.
At 1 year, the overall survival rate was 88.5% (95% CI, 80.2%-93.5%). The median overall survival was also not yet reached.
The most common grade 3/4 adverse events (AEs) were hematologic and observed in 99.0% of all patients, consisting of neutropenia in 94.8%, anemia in 68.0%, leukopenia in 60.8%, and thrombocytopenia in 59.8%. The median time to recovery of these grade 3/4 cytopenias was 2 weeks for neutropenia and 4 weeks for thrombocytopenia. The rate of any-grade infections was 57.7%, and the most common grade 3/4 infections were pneumonia (8.2%) and sepsis (4.1%).
Grade 3/4 non-hematologic toxicities were not common in the study, including hypophosphatemia at 7.2%, fatigue at 5.2%, aspartate aminotransferase increase at 5.2%, and hyponatremia at 4.1%.
Additionally, cytokine release syndrome (CRS), a common CAR T-cell therapy–related AE, was reported in 94.8% of patients at any grade, but only 4.1% were grade 3/4 in severity.
“One distinguishing aspect of this study is the median time to onset of CRS, which is 7 days, with 89% of these patients having CRS at day 4 or later and 74% of these patients having CRS at day 6 or later, opening the possibility of outpatient administration. This may be explained by the fact that the maximum peripheral expansion of cilta-cel occurred generally around a median of 13 days,” Madduri said.
Tocilizumab and corticosteroid support were required in 69.1% and 21.6% of patients, respectively. CRS resolved in 98.9% of all patients within 14 days of onset.
Neurotoxicity, another known complication of CAR T-cell therapies, was reported in 20.6% of patients at any grade and of grade 3 or higher in 10.3%. Specifically, immune effector cell–associated neurotoxicity syndrome (ICANS) cases were reported in 16.5% at any grade and of grade 3 or higher in 2.1%. All ICANS occurred within a median of 8 days (range, 3-12) and resolved within a median of 4 days (range, 1-12).
Other neurotoxicities, which were reported in 12 patients (12.4%), occurred after resolution of CRS or ICANS and included 5 patients with movement and/or neurocognitive changes and 7 with nerve palsy or peripheral motor neuropathy; 6 of these resolved. In the other 6 patients, 1 patient died from complications of the AE, 4 died of other causes, and 1 has ongoing neurotoxicity. The median time to onset for these toxicities was 27 days (range, 11-108) with recovery in a median of 75 days (range, 2-160).
“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these CAR T cells. So we did implement some mitigation strategies in our subsequent CARTITUDE development program allowing patients to have more chemotherapy, having more aggressive steroids for ICANS, like early intervention and extensive monitoring,” Madduri said in the question-and-answer portion of the session following her presentation.
A total of 14 patients died during the study within 45 to 694 days of infusion. Five patient deaths were due to progressive disease, 3 were due to AEs that were not related to treatment, and 6 were due to AEs considered to be related to treatment with cilta-cel. These AEs included sepsis and/or septic shock in 2 patients, and CRS or hemophagocytic lymphohistiocytosis, lung abscess, respiratory failure, and neurotoxicity in 1 patient each.
Cilta-cel is continuing to be studied in patients with multiple myeloma in other clinical trials, including in earlier-line settings. Additionally, both the CARTITUDE-2 (NCT04133636) and CARTITUDE-4 (NCT04181827) studies are considering whether cilta-cel can safely be given in an outpatient setting.
In December 2019, cilta-cel was granted an FDA breakthrough therapy designation for the treatment of patients with previously treated multiple myeloma based on earlier results of the CARTITUDE-1 trial.3